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Antiviral Res . Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir

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  • Antiviral Res . Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir


    Antiviral Res


    . 2021 Feb 10;105035.
    doi: 10.1016/j.antiviral.2021.105035. Online ahead of print.
    Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir


    Mira C Patel 1 , Anton Chesnokov 1 , Joyce Jones 1 , Vasiliy P Mishin 1 , Juan A De La Cruz 1 , Ha T Nguyen 2 , Natosha Zanders 3 , David E Wentworth 1 , Todd C Davis 1 , Larisa V Gubareva 4



    AffiliationsFree article

    Abstract

    Pimodivir exerts an antiviral effect on the early stages of influenza A virus replication by inhibiting the cap-binding function of polymerase basic protein 2 (PB2). In this study, we used a combination of sequence analysis and phenotypic methods to evaluate pimodivir susceptibility of influenza A viruses collected from humans and other hosts. Screening PB2 sequences for substitutions previously associated with reduced pimodivir susceptibility revealed a very low frequency among seasonal viruses circulating in the U.S. during 2015-2020 (<0.01%; 3/11,934) and among non-seasonal viruses collected in various countries during the same period (0.2%; 18/8971). Pimodivir potently inhibited virus replication in two assays, a single-cycle HINT and a multi-cycle FRA, with IC50 values in a nanomolar range. Median IC50 values determined by HINT were similar for both subtypes of seasonal viruses, A (H1N1)pdm09 and A (H3N2), across three seasons. Human seasonal viruses with PB2 substitutions S324C, S324R, or N510K displayed a 27-317-fold reduced pimodivir susceptibility. In addition, pimodivir was effective at inhibiting replication of a diverse group of animal-origin viruses that have pandemic potential, including avian viruses of A (H5N6) and A (H7N9) subtypes. A rare PB2 substitution H357N was identified in an A (H4N2) subtype poultry virus that displayed >100-fold reduced pimodivir susceptibility. Our findings demonstrate a broad inhibitory activity of pimodivir and expand the existing knowledge of amino acid substitutions that can reduce susceptibility to this investigational antiviral.

    Keywords: Drug susceptibility; H7N9; PB2 inhibitor; Pandemic potential; Pimodivir; Zoonotic influenza.

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